Retroviral insertional activation of the Fli-3 locus in erythroleukemias encoding a cluster of microRNAs that convert Epo-induced differentiation to proliferation

Abstract

MicroRNAs (miRNAs) are a newly discovered class of posttranscriptional regulatory noncoding small RNAs. Recent evidence has shown that miRNA misexpression correlates with progression of various human cancers. Friend erythroleukemia has been used as an excellent system for the identification and characterization of oncogenes and tumor suppressor genes involved in neoplastic transformation. Using this model, we have isolated a novel integration site designated Fli-3, from a Friend murine leukemia virus (F-MuLV)–induced erythroleukemia. The Fli-3 transcription unit is a murine homologue of the human gene C13orf25 that includes a region encoding the mir-17–92 miRNA cluster. C13orf25 is the target gene of 13q31 chromosomal amplification in human B-cell lymphomas and other malignancies. The erythroleukemias that have acquired either insertional activation or amplification of Fli-3 express higher levels of the primary or mature miRNAs derived from mir-17–92. The ectopic expression of Fli-3 in an erythroblastic cell line switches erythropoietin (Epo)–induced differentiation to Epo-induced proliferation through activation of the Ras and PI3K pathways. Such a response is associated with alteration in the expression of several regulatory factors, such as Spi-1 and p27 (Kip1). These findings highlight the potential of the Fli-3 encoding mir-17–92 in the development of erythroleukemia and its important role in hematopoiesis.